1. Field of the Invention
The present invention relates to a process for the preparation of S-(−)-amlodipine, more specifically, to a process for the preparation of S-(−)-amlodipine from (R,S)-amlodipine in industrial-scale using L-(+)-tartaric acid, which is much cheaper than D-(−)-tartaric acid.
2. Description of the Related Art
Amlodipine, with a chemical name of 3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate, is a potent and long-acting calcium channel blocker useful as an anti-ischaemic and anti-hypertensive agent. It is known that two types of enantiomers of amlodipine have different pharmacological profiles. S-(−)-isomer is a more potent calcium channel blocker than R-(+)-isomer, while the R-(+)-isomer also exhibits an activity in the treatment or prevention of atherosclerosis.
J. Med. Chem. (1986) 29 1696 discloses a process for the preparation of the two enantiomers of amlodipine via separation of the diastereomeric azide esters, and EP 331,315 A1 discloses the use of cinchonidine salts for the resolution of intermediates to eventually give enantiomerically pure amlodipine isomers. J. Med. Chem. (1992) 35 3341 discloses a chromatographic separation of diastereomeric amide isomers.
Further, WO 95/25722 discloses a method for the separation of the (R)-(+)- and (S)-(−)-isomers of amlodipine from mixtures thereof, which comprises reacting the mixture of isomers with either L-(+)- or D-(−)-tartaric acid in dimethyl sulfoxide (DMSO) for the preparation of, respectively, a DMSO solvate of an L-tartrate salt of (R)-(+)-amlodipine, or a DMSO solvate of a D-tartrate salt of (S)-(−)-amlodipine.
In order to manufacture (S)-(−)-amlodipine, having a more potent calcium channel blocking activity, the process according to WO 95/25722 employs D-tartaric acid. However, the fact that D-(−)-tartaric acid is very expensive compared to L-(+)-tartaric acid is unfavorable for industrial-scale mass production of (S)-(−)-amlodipine.
Therefore, a method of industrial-scale mass production of (S)-(−)-amlodipine has been in demand.